Design of tuberculosis vaccine trials under financial constraints

KEYWORDS:

• Tuberculosis
• vaccine
• R&D
• correlates of protection
• BCG

Editorial

In the history of mankind, never before have more people developed tuberculosis (TB) than today. According to the World Health Organization (WHO), around 9.6 million incident cases and 1.5 million deaths were attributed to TB in 2014 [1]. In 2015, the WHO launched the End-TB strategy that ambitiously aims at reducing 90% of TB incidence and 95% of TB mortality by 2035 [2]. However, this scenario will only be realistic if better diagnostic tests, better treatments, and above all, better TB vaccines than the attenuated Mycobacterium bovis Bacille Calmette Guérin (BCG) vaccine are available for broad implementation in high-endemic countries.

BCG, which was developed almost a century ago, is the most widely used vaccine in the world, but its impact on TB control is clearly inadequate. Its effect is mainly on reduction of severe forms of the disease in children rather than on prevention of active, pulmonary TB in adolescents and adults, who are responsible for transmission as well as the majority of morbidity and mortality from this devastating disease [3]. Renewed efforts of the scientific community during the past two decades achieved considerable advances in TB vaccine research, with 14 candidates currently in the clinical development pipeline [4]. However, poor efficacy outcomes of the MVA85A trials [5,6] have led to considerable disappointment in the TB research community and among donors.

Worryingly, a recent report showed that in 2014, a total of 111.3 million USD were spent on TB vaccine research [7], which is not even 30% of the estimated needs established by the Global Plan to Stop TB [8]. These financial constraints inevitably require a rethinking of strategies for vaccine candidate discovery, optimization, and clinical evaluation, including the possibility of more cost-efficient clinical trial designs. Thus, the current situation has led to a ‘shift to the left’ in the overall TB vaccine Research and Development strategy of the Bill and Melinda Gates Foundation, the major TB vaccine funder. This shift translates into a greater focus on discovery and preclinical evaluation in advanced nonhuman primate models rather than on clinical development. An important bottleneck for the TB vaccine research field is that correlates of immune protection from TB have not been identified. In consequence, the tools for rationally de-risking candidates before entry into large, expensive efficacy trials [9] are inadequate, resulting in high costs and long timelines for TB vaccine development.

To de-risk candidates earlier in clinical development and at lower cost, the following measures could be considered.

Overall approach

Depending on the expected mechanism of action of a given TB vaccine, candidates have been traditionally classified into three broad categories: prevention of infection (POI), prevention of disease, and host-directed therapy. The latter are intended for the treatment of complicated forms of TB [10], with potentially lower impact for TB control. Most vaccines in the pipeline are designed with focus on the prevention of active TB disease [11].

Nonetheless, several current vaccine designs try to address both uninfected and already infected individuals, the so-called multistage vaccines [12,13]. The rationale is that by targeting antigens expressed by Mycobacterium tuberculosis during both latent infection and active disease, prevention for both populations could be achieved. However, a focus on POI vaccines, aiming at avoiding that naive populations be infected would have considerable public health impact in the long term, given that infection be preventable even in the 10% of those who, if became infected, would go on to develop the disease [14]. Beyond the potential plausibility for the design of protective preinfection vaccines [14], these types of trials require smaller sample sizes and shorter duration in high-endemic countries [15], given that the forces of transmission are high and high conversion rates could be detectable by interferon-γ release assays [16].

For those studies aiming at preventing TB disease, the most impactful approach in the short-medium term for TB control, smaller sample sizes, and shorter duration could be achieved if studies were performed in high-risks groups, such as individuals with latent TB infection, miners, prisoners, health-care workers, people living with HIV, recent contacts of TB patients, or previously treated patients. Although the involvement of these populations in TB vaccine trials is not exempt of ethical and operational issues, these groups are known to have higher risk of developing the disease. The latter are the target population for the so-called prevention of recurrence (POR) studies, which represent a potentially efficient approach, given that trials could be done with relatively low-sample sizes. Given that 91% of recurrences might occur during the first year after TB treatment completion and a high proportion of recurrences in high-transmission settings, vaccine trials designs including just 450 participants per study group with 12-month follow-up could be deemed sufficiently powered [15]. However, identifying these patients and ensuring they fulfill the definition of ‘cured’ are issues that would also need to be addressed.

Head-to-head testing

There is a need to rationalize the selection of the most promising candidates to enter further phases of clinical development. There are many constructs with similar immunological principles. Head-to-head comparisons at preclinical phase of evaluation and earlier stages of clinical development could help triage candidates before entry to larger clinical trials. Although this strategy is not new, head-to-head testing has not been practiced at early clinical stage. Reasons might include the independent development pathways followed by vaccine sponsors (owners) or the current absence of a global portfolio management, a global framework of collaboration between the institutions uncharged of supporting vaccine development research (TBVI, Aeras, European Investment Bank, EDCTP), whose foundation and main mandate have been recently discussed [17].

Adaptive clinical trial design

Some of the latest phase II trials have been designed in an adaptive fashion. This means that the trial might be modified (‘adapted’) or stopped depending on interim immunogenicity results. This can be especially useful for dose trials, which include dose-selection phases, so they start new recruitment in specific subgroups based on the immunogenicity or safety evaluations of a previous (typically lower) dose. At the same time, there is the ability to expand follow-up of those who participated in the dose-selection phases of the trial to increase enrollment efficiency and save time if the trial expands to an efficacy phase.

Human challenge model

Another approach that would reduce sample size and costs would be a human challenge model, in which participants would be infected under controlled conditions with a modified, safe strain of M. tuberculosis. A human challenge model is being used widely in malaria vaccine research where a 3-day course of antimalarials is curative, but for TB there are serious safety concerns that prohibit human challenge. Only one challenge model has been tested – using BCG intradermally as the challenge strain [18]. Further challenge studies with attenuated M. tuberculosis strains at lung level could be very informative for vaccine research, increasing its efficiency especially for testing POI candidates, but safety of the model would have to be assured first.

The sample population to be targeted deserves attention. Just a few years ago, most trials aimed at targeting young children (newborns and infants), mostly due to (a) a predefined strategy based on pre-exposure (BCG replacement or BCG prime-novel vaccine boost), (b) the fact that there is a high-TB burden below 5 years of age, (c) the assumption that a candidate could achieve lifelong protection, and (d) the logistical and practical reasons associated with the deployment of vaccines in this population subgroup. However, there is evidence that the greatest impact for TB control will likely occur if an effective vaccine is applied in adolescence and young adulthood [19]. This makes testing these populations a reasonable and efficient alternative. In fact, based on this assumption, most of the studies in clinical development now target adolescents or young adults.

Biorepositories

Due to the expensive nature of clinical trials, not enough stress is given to the importance of collecting extra samples from recruited patients at all study visits for biobanking purposes. This should be taken into account at protocol development. Samples from a given trial could be useful for analyzing novel trial endpoints not previously envisaged or studying correlates of protection with samples at different time points. If successful, such studies would enable streamlining of future TB vaccine development programs [17].

Final remarks

It is clear that the lack of known correlates of protection hinder the achievement of an effective TB vaccine at present. Most efforts dedicated to finding these correlates have been directed at the evaluation of T-cell-immunity-associated endpoints – immune responses known to have some role in preventing TB disease [20]. Other immune-related biomarkers, related to B cell or innate immunity, as well as in-vitro growth inhibition assays are currently being explored. Similarly, the formulation of new vaccine constructs (discovery) still needs to be more diverse, and should explore other targets including subdominant and nonclassical antigens.

Although more efficiency can be applied at any level of the TB vaccine research stages, coming up with the long-awaited silver bullet for TB control will not happen unless available funding is expanded. Though not a dose–effect relationship, there are many reasons to believe that an increase in funding will enhance our chances to obtain an effective vaccine, the only intervention that could remarkably accelerate the decrease in TB incidence worldwide. Undoubtedly, if funding agencies shrink the budgets for the purpose, TB vaccines will remain a hopeless dream.

Financial & competing interests disclosure

M Ruhwald is employed by SSI a governmental non-for profit research organization holding IPR on several vaccine candidates in pre- and clinical development. C Lange reports personal fees from Abbvie, MSD, Becton Dickinson, Chiesi, Gilead, and Janssen outside the submitted work. C Lange is supported by the German Center for Infection Research (DZIF). The authors have no other relevant affiliations or financial involvement with any organization or entity with financial interest or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Acknowledgment

The authors thank Ann Ginsberg (Aeras) for her valuable comments to the draft manuscript.